Active substance patch for the release of estradiol to the skin

ABSTRACT

An active substance patch releasing estradiol to the skin is characterized by the fact that it consists essentially of a backing layer and an attached active substance reservoir which comprises pressure sensitive adhesive and in which the active substance is at least partially soluble, and of a removable protective layer covering the adhesive film, the active substance reservoir being a polymer matrix which--in order to improve the bioavailability of the estradiol--comprises an added penetration enhancer of the general formula: ##STR1## wherein R=--CH 2  OH or --CH 2  --O--CH 2  --CHOH--CH 2  OH.

This application is a 371 of PCT/EP94/00670, filed Mar. 7, 1994.

The present invention relates to an active substance patch for therelease of estradiol to the skin consisting essentially of a backinglayer, an active substance reservoir which is connected to the backinglayer, and which comprises a pressure sensitive adhesive and wherein theactive substance is at least partially soluble, and a removableprotective layer covering the adhesive film.

Estradiol is required to alleviate the symptoms of menopause,oophorectomy and primary pituitary failure. For this reason there is asignificant need for an estradiol replacement therapy for alleviatingboth menopausal symptoms, such as hot flushes, nervous discomfort, ordisturbed sleep, and osteoporosis (loss of bone mass) andatherosclerosis accompanying estradiol deficiency.

When estradiol, in particular 17-β-estradiol, is administered orally,the absorption is unsatisfactory because of its low water-solubilityafter oral administration. Due to the rapid metabolism of 17-β-estradiolthrough the liver high doses are required, frequently resulting inundesired side effects, such as sickness and thrombo-embolism. Thereforeit is necessary to improve the means and methods of the estradioltherapy.

The transdermal route of parenteral administration allows theadministration of lower doses of 17-β-estradiol in order to avoid thefirst-pass-metabolism. With this administration form the metabolism ofrelatively large amounts of estradiol is avoided.

Thus, the transdermal route offers advantages over other routes.Transdermal systems for the administration of a large variety ofdifferent active substances or other medicinal agents are exemplified inU.S. Pat. Nos.: 4,906,169; 5,023,084; 4,818,540 and 4,746,515 and in WO91/05529. With respect to their size, thickness and active substanceutilization, the transdermal systems according to the state of the artare not satisfactory since only a small portion of the applied dose isutilized therapeutically. Despite the developments made in the modes ofadministration, there is a need for further improved techniques toprovide the users of said drug with another constant estradiol level ina favorable, i.e. transdermally applicable, mode of dosage. In principleit is known to apply estradiol transdermally, however, for the abovereasons it is desirable to develop improved transdermal processes forthe administration of estradiol.

It is the object of the present invention to provide an active substancepatch for releasing estradiol to the skin, which has a pressuresensitive adhesive-containing active substance reservoir in which theactive substance is at least partially soluble and which deliverstherapeutically effective estradiol rates at an increasedbioavailability as compared to the oral or intramuscular administrationof the active substance. The active substance patch is to provide afavorable therapy with an improved compliance, in particular owing toits advantageous mode of dosage.

In an active substance patch of the kind described herein this object isachieved according to the present invention by the fact that the activesubstance reservoir is a polymer matrix to which--in order to improvethe bioavailability of the estradiol--a penetration enhancer of thegeneral formula ##STR2## is added, in which R=--CH₂ OH or --CH₂ --O--CH₂--CHOH--CH₂ OH, corresponding to the compounds monoisopropylideneglycerol (MIPG) or monoisopropylidene diglycerol (MIPD).

By adding the penetration enhancer according to the invention thebioavailability of the active substance is considerably improved toadvantage, allowing the application of a lower active substance dose ascompared to known systems. The active substance patch prepared accordingto the present invention provides the required estradiol dose from atransdermal system.

According to one embodiment of the present invention the activesubstance patch additionally comprises one or more other compoundsfurther intensifying the action of the penetration improving agent.

For example, it is provided that these penetration-supporting compoundsbe selected from the group consisting of polyethylene glycols, glycolsand/or pyrrolidones and/or polymers of pyrrolidone derivatives, forexample Kollidon® 25 (BASF, homopolymer of N-vinyl-2-pyrrolidone).Compounds of the first-mentioned groups, for example, include propyleneglycol (PG), 2-pyrrolidone (2-P), and polyethylene glycol 400 (PEG 400).

According to another embodiment it is provided that the activesubstance-containing reservoir comprises homo and/or copolymers ofacrylates and/or methacrylates.

Additionally, the active substance-containing reservoir may comprise upto 3% by weight of a filler. The concentration of estradiol in thereservoir advantageously amounts to 0.7-3.5% by weight.

In this connection the weight ratio between estradiol and penetrationaccelerator may amount to 1:3 to 1:15.

According to another embodiment it is provided that the activesubstance-containing reservoir comprises up to 5% by weight of awater-absorbing polymer.

It has proven to be advantageous that the estradiol is 17-β-estradiol.

The present invention utilizes the principles of the transdermal activesubstance release to the organism via the skin and is directed to theadministration of estradiol.

Embodiments of the present invention employ a backing layer, which maybe manufactured from a suitable material which is impermeable to theactive substance and to other components of the reservoir layer. Thisbacking layer fulfils the required protective and supportive function.Suitable materials used for the backing layer may be polyester,polyvinyl chloride, polyamide, polyethylene, polypropylene, andpolyurethane, as well as composites of these materials. Metal foils,e.g. of aluminum, may also be used, either alone or laminated with apolymeric substance. An active substance-containing polymer matrixmanufactured according to the present invention comprises the activesubstance distributed in a pressure sensitive adhesive base substance;said base substance may, for instance, be based on polyacrylates orpolymethacrylates, polyurethanes, silicones, polyisobutylenes,polysiloxanes, or styrene-isoprene-styrene-copolymers, and on copolymersof ethylene with vinyl acetate or acrylic acid derivatives. In thismanner it is ensured that the active substance is in close contact withthe skin.

The mentioned enhancers may be used individually or in combination. Theyare distributed over the whole pressure sensitive adhesive matrixcomprising the active substance.

The pressure sensitive adhesive matrix is laminated on a suitableremovable protective layer. A protective layer suitable for suchlaminates consists of the same materials as those described for thebacking layer; however they have been rendered removable by conventionalsiliconization. Further removable protective layers may consist ofpolyethylene laminated with an aluminum foil, the polyethylene sideprovided with the pressure sensitive adhesive matrix being siliconized;other protective layers consist of polytetrafluoroethylene, pretreatedpaper, cellophane and the like.

Manufacture of the system

BRIEF DESCRIPTION OF THE DRAWING

The preferred embodiment of the present invention is illustrated inFIGURE 1 representing a cross section of the TTS according to theinvention. In this FIGURE 1 (1) represents the backing layer, (2) thereservoir comprising the active substance and the enhancer, and (3) theremovable protective layer.

The active substance-comprising reservoir may be formed of polymers ofacrylates and methacrylates. The active substance-containing reservoirmay also comprise a water-absorbing polymer, e.g. a homopolymer ofN-vinyl-2-pyrrolidone, as well as fillers, such as Aerosil® or Syloid®.

The proportion of the incorporated filler may range between 1 and3%-wt., preferably between 1.5 and 2%-wt.

The proportion of the incorporated water-absorbing polymer may amount toup to 5%-wt.

The active substance and the enhancer(s) are combined with each other atdifferent proportions ranging between 1:3 and 1:15, and they areincorporated either by dissolution or dispersion of the activesubstance-enhancer-combination in a polyacrylate solution. The resultingmixture is stirred until a homogeneous dispersion results. The resultantflowable preparation is distributed on a surface and the solventevaporated so that a solvent-free matrix is obtained comprising theactive substance and the enhancer. This matrix is in the form of a film.

A typical embodiment of the present invention comprises between 0.7% and3.5% 17-β-estradiol (based on percent by weight of the film) and between8%-wt. and 28%-wt. enhancer.

The following examples illustrate the realization of the presentinvention in a transdermal system of the matrix type, in which theadministration of the active substance is effected through themonolithic or laminated matrix system in a diffusion-controlled manner.In addition, the present invention may also be used in the membrane typewherein the active substance diffusion from the reservoir is controlledby the membrane, the reservoir being filled with a liquid or a semisolidsubstance.

EXAMPLES Examples 1-6

According to the present invention monolithic matrix systems weremanufactured as follows: The enhancer(s) was/were intensely mixed withthe active substance and silicon dioxide filler (by Grace GmbH) and/orthe water-absorbing polymer Kollidon® 25 (by BASF). A solution of thepolyacrylate pressure sensitive adhesive (Durotak 280-2516, by NationalStarch) was added thereto, typical solvents for the polymer comprisinglower alcohols, such as ethanol and methanol, lower alkane esters, suchas ethyl acetate, and alkanes, such as heptane. This mixture was stirreduntil a homogeneous mass formed. This adhesive mass was allowed to standfor 15 min. and then spread on a siliconized polyester sheet (HostaphanRN 100) at a thickness of 200 μm, the solvent was removed by drying inan oven at 50° C. The resultant solvent-free matrix was laminated with apolyester backing layer (Hostaphan RN 15). Patches of 2.54 cm² in sizewere cut from this laminate and assessed byin-vitro-skin-permeation-studies.

The siliconized protective layer was removed and the backing layer withthe adhering active substance-containing matrix pressed to thestratum-corneum-side of excized naked mice skin. Then, the skin togetherwith the attached system was introduced into a Franz-diffusion-cell. Thereceiver medium, which comprised 40% polyethylene glycol in water, wasstirred and. Constantly kept at a temperature of 37° C. At predeterminedtime intervals samples were taken out and the volumes were immediatelyreplaced by fresh receiver liquid which had previously been brought intoan equilibrium state. The samples were examined by HPLC. The activesubstance flux was determined by the gradient of the active substanceamount present in cumulated form in the receptor medium, which was putin relation to time. The flux values of Examples 1-6 are listed inTable 1. All systems listed in Table 1 had acceptable flux values,however, the best results were achieved when MIPD was used alone.

Example 7

Monolithic matrix systems were manufactured according to the inventionand used with excised naked guinea pig skin.In-vitro-permeation-experiments were carried out to determine thebioequivalence of the different systems. The commercial transdermalsystem Estraderm-25 TTS was used as standard. In order to compare thebioequivalence of the systems, the flux values were expressed aspercentage of the applied dose. The data is listed in Table 2.

The results show that the best bioequivalence was obtained with amonolithic matrix system comprising MIPD as penetration enhancer.Although this enhancer can act in the same manner as ethanol in theEstraderm-TTS, i.e. as a solvent for the active substance, asurprisingly high flux was achieved in this monolithic system. In thismanner it is possible to reduce the size of the TTS (to approximately 4cm²) and still release therapeutically effective estradiol doses (50 μgwithin 24 hours).

Example 8

If the MIPD is replaced by MIPG comparable results are obtained.

                                      TABLE 1                                     __________________________________________________________________________    In vitro flux of estradiol through naked mice skin                            (per cent by weight of the solvent-free matrix)                               Example                                                                            Polyacrylate                                                                        SiO.sub.2                                                                        PG                                                                              Estradiol                                                                          MIPD                                                                              2-P                                                                             PEG 400                                                                            Flux (μg cm.sup.-2 h.sup.-1)               __________________________________________________________________________    1    70    1.2                                                                              12                                                                              1.8  15  / /    0.523 ± 0.01                               2    70    1.2                                                                              15                                                                              1.8  12  / /    0.523 ± 0.13                               3    70    1.2                                                                              / 1.8  12  15                                                                              /    0.500 ± 0.03                               4    70    1.2                                                                              / 1.8  12  / 15   0.397 ± 0.04                               5    70    1.2                                                                              17                                                                              1.8  10  / /    0.523 ± 0.08                               6    70    2.65                                                                             / 1.8  25.6                                                                              / /    0.612 ± 0.09                               __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    In vitro flux of estradiol through naked guinea pig skin                              (per cent by weight of the solvent-free matrix)                       Example Polyacrylate                                                                        SiO.sub.2                                                                        PG                                                                              Estradiol                                                                          MIPD                                                                              Kollidon-25                                                                         Flux (%/h)                                  __________________________________________________________________________    7       70    1.2                                                                              15                                                                              1.8  12  /     12.56                                       8       70    2.65                                                                             / 1.8  25.6                                                                              /     18.36                                       9       82.9  /  / 2.7  10.1                                                                              4.2   21.61                                       Estraderm.25                      4.24*                                       TTS (= prior art)                                                             __________________________________________________________________________     *calculated from the flux indicated in WO 91/05529                       

I claim:
 1. An active substance patch for the release of estradiol tothe skin consisting essentially of a backing layer and an activesubstance reservoir connected thereto which comprises estradiol and apressure sensitive adhesive and in which the estradiol is at leastpartially soluble, and a removable protective layer covering theadhesive film, wherein the active substance reservoir is a polymermatrix to which, in order to improve the bioavailability of theestradiol, a penetration enhancer of the formula ##STR3## is added,wherein R=--CH₂ OH or --CH₂ --O--CH₂ --CHOH--CH₂ OH,the weight ratio ofestradiol to penetration enhancer being 1:3 to 1:15.
 2. The activesubstance patch according to claim 1 wherein the activesubstance-containing reservoir comprises up to 3%-wt. of a filler. 3.The active substance patch according to claim 1 wherein theconcentration of estradiol in the reservoir amounts to 0.7 to 3.5%-wt.4. The active substance patch according to claim 1 wherein the activesubstance-containing reservoir comprises up to 5%-wt. of awater-absorbing polymer.
 5. The active substance patch according toclaim 1 wherein the estradiol is 17-β-estradiol.
 6. The active substancepatch according to claim 1 wherein the active substance reservoiradditionally comprises at least one compound intensifying the action ofthe penetration enhancer.
 7. The active substance patch according toclaim 6 wherein additional penetration enhancing compounds are selectedfrom the group consisting of polyethylene glycols, glycols,pyrrolidones, vinyl pyrrolidone polymers and mixtures thereof.
 8. Theactive substance patch according to claim 1 wherein the activesubstance-containing reservoir comprises homopolymers or copolymers ofan acrylate or methacrylate or mixtures thereof.